tbuckley/cabot-search huggingface dataset:
Barriers to Electronic Patient-Reported Outcome Measurement Among Patients with Cancer and Limited English Proficiency
Authors: Elena Garcia Farina, Jessi Rowell, Anna Revette, Ellana K. Haakenstad, Jessica L. F. Cleveland, Rachel Allende, Michael Hassett, Deborah Schrag, Nadine J. McCleary
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Often electronic tools are built with English proficient (EP) patients in mind. Cancer patients with limited English proficiency (LEP) experience gaps in care and are at risk for excess toxic effects if they are unable to effectively communicate with their care team. <h3>Objective</h3> To evaluate whether electronic patient-reported outcome tools (ePROs) built to improve health outcomes for EP patients might also be acceptable for LEP patients in the context of oral cancer-directed therapies (OCDT). <h3>Design, Setting, and Participants</h3> This qualitative study was conducted at a single National Cancer Institute–designated comprehensive cancer center. In 2019, English-speaking and Spanish-speaking LEP patients with cancer receiving oral chemotherapies were recruited to participate in a qualitative focus group examining patient attitudes toward ePROs and electronic tools that are used to manage adherence and symptoms related to oral therapies. Six focus groups were held for EP patients and 1 for Spanish-speaking LEP patients. LEP was defined as patients who self-identified as needing an interpreter to navigate the health care system. Data analysis was performed April through June of 2019. <h3>Exposures</h3> Enrolled patients participated in a focus group lasting approximately 90 minutes. <h3>Main Outcomes and Measures</h3> The perspectives of patients with cancer treated with oral chemotherapies on integrating ePROs into their care management. <h3>Results</h3> Among the 46 participants included in the study, 46 (100%) were White, 10 (22%) were Latinx Spanish-speaking, 43 (93%) were female, and 37 (80%) were aged at least 50 years or older. Among the 6 focus groups with 6 to 8 EP patients (ranging from 6 to 8 participants) and 1 focus group with 10 Spanish-speaking LEP patients, this qualitative study found that EP and LEP patients had different levels of acceptability of using technology and ePRO tools to manage their OCDT. EP patients felt generally positive toward OCDT and were not generally interested in using electronic tools to manage their care. LEP patients generally disliked OCDT and welcomed the use of technology for health management, particularly when addressing gaps in symptom management by their oncology clinicians. <h3>Conclusions and Relevance</h3> Although most electronic interventions target EP patients, these findings reveal the willingness of LEP patients to participate in technology-based interventions. Expanding ePROs to LEP patients may help to manage gaps in communication about treatment and potential adverse events because of the willingness of LEP patients to use ePRO tools to manage their health. This qualitative assessment is a strategic step in determining the resources needed to narrow the digital health gap and extend the value of PROs to the LEP oncology population.
Monkeypox: New clinical symptoms are identified in confirmed cases
Authors: Jacqui Wise
Journal: BMJ (2022)

There is an increasing tendency for administrators and government to expect both the health services and the education service to 9show results9 for the investment of public money in them. One response to this has been the growing commitment to 9health promotion9, where measurable objectives may be set in terms of desired behaviour (stopping smoking, breast self-examination, child immunisation etc) and where evaluation can be made on the evidence of statistical improvement. Health workers use the term 9promotion9 in a variety of ways which seem to be as confusing to them as they are to their clients --the general public. Since successful promotion is likely to depend on the 9hard sell9 (and since the methodology and aims of this may be incompatible with those of health education) this paper looks at some of the questions which the customer might wish to ask the salesman before deciding whether or not to buy.
And-1 Coordinates with the FANCM Complex to Regulate Fanconi Anemia Signaling and Cisplatin Resistance
Authors: Yi Zhang, Jing Li, Yuan Zhou, Zhuqing Li, Changmin Peng, Huadong Pei, Wenge Zhu
Journal: Cancer Research (2022)

Abstract The Fanconi anemia (FA) pathway is essential for repairing DNA interstrand crosslinks (ICL). ICLs induce stalled DNA replication forks and trigger activation of the FA pathway by promoting recruitment of the FANCM/FAAP24/MHF complex to ICL sites. Given that stalled replication forks are proximal to ICL sites, fork-associated proteins may coordinate with FA factors to rapidly sense ICLs for activation of FA signaling. Here we report that And-1, a replisome protein, is critical for activation of the FA pathway by sensing ICL-stalled forks and recruiting the FANCM/FAAP24 complex to ICLs. In response to ICLs, And-1 rapidly accumulated at ICL-stalled forks in a manner dependent on ataxia telangiectasia and Rad3-related protein–induced phosphorylation at T826. And-1 phosphorylation triggered an intramolecular change that promoted the interaction of And-1 with FANCM/FAAP24, resulting in recruitment of the FANCM/FAAP24 complex to ICLs. Furthermore, p-T826 And-1 was elevated in cisplatin-resistant ovarian cancer cells, and activated And-1 contributed to cisplatin resistance. Collectively, these studies elucidate a mechanism by which And-1 regulates FA signaling and identify And-1 as a potential target for developing therapeutic approaches to treat platinum-resistant ovarian cancer. Significance: This work shows that phosphorylation of And-1 by ATR activates Fanconi anemia signaling at interstrand crosslink–stalled replication forks by recruiting the FANCM/FAAP24 complex, revealing And-1 as a potential therapeutic target in cancer.
Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis
Authors: Ruben Mesa, Claire Harrison, Stephen T. Oh, Aaron T. Gerds, Vikas Gupta, John Catalano, Francisco Cervantes, Timothy Devos, Marek Hus, Jean-Jacques Kiladjian, Ewa Lech-Maranda, Donal McLornan, Alessandro M. Vannucchi, Uwe Platzbecker, Mei Huang, Bryan Strouse, Barbara Klencke, Srdan Verstovsek
Journal: Leukemia (2022)

Abstract Janus kinase inhibitors (JAKi) approved for myelofibrosis provide spleen and symptom improvements but do not address anemia, a negative prognostic factor. Momelotinib, an inhibitor of ACVR1/ALK2, JAK1 and JAK2, demonstrated activity against anemia, symptoms, and splenomegaly in the phase 3 SIMPLIFY trials. Here, we report mature overall survival (OS) and leukemia-free survival (LFS) from both studies, and retrospective analyses of baseline characteristics and efficacy endpoints for OS associations. Survival distributions were similar between JAKi-naïve patients randomized to momelotinib, or ruxolitinib then momelotinib, in SIMPLIFY-1 (OS HR = 1.02 [0.73, 1.43]; LFS HR = 1.08 [0.78, 1.50]). Two-year OS and LFS were 81.6% and 80.7% with momelotinib and 80.6% and 79.3% with ruxolitinib then momelotinib. In ruxolitinib-exposed patients in SIMPLIFY-2, two-year OS and LFS were 65.8% and 64.2% with momelotinib and 61.2% and 59.7% with best available therapy then momelotinib (OS HR = 0.98 [0.59, 1.62]; LFS HR = 0.97 [0.59, 1.60]). Baseline transfusion independence (TI) was associated with improved survival in both studies (SIMPLIFY-1 HR = 0.474, p = 0.0001; SIMPLIFY-2 HR = 0.226, p = 0.0005). Week 24 TI response in JAKi-naïve, momelotinib-randomized patients was associated with improved OS in univariate (HR = 0.323; p &lt; 0.0001) and multivariate (HR = 0.311; p &lt; 0.0001) analyses. These findings underscore the importance of achieving or maintaining TI in myelofibrosis, supporting the clinical relevance of momelotinib’s pro-erythropoietic mechanism of action, and potentially informing treatment decision-making.
Tumor cell SYK expression modulates the tumor immune microenvironment composition in human cancer via TNF-α dependent signaling
Authors: Adam Aguirre-Ducler, Nicole Gianino, Franz Villarroel-Espindola, Shruti Desai, Daiwei Tang, Hongyu Zhao, Konstantinos Syrigos, William L Trepicchio, Karuppiah Kannan, Richard C Gregory, Kurt A Schalper
Journal: Journal for ImmunoTherapy of Cancer (2022)

The expression of SYK in cancer cells has been associated with both tumor promoting and tumor suppressive effects. Despite being proposed as anticancer therapeutic target, the possible role of SYK in modulating local adaptive antitumor immune responses remains uncertain. Using detailed analysis of primary human tumors and in vitro models, we reveal the immunomodulatory effect of SYK protein in human solid cancer. We spatially mapped SYK kinase in tumor cells, stromal cells and tumor-infiltrating leukocytes (TILs) in 808 primary non-small cell lung carcinomas (NSCLCs) from two cohorts and in 374 breast carcinomas (BCs) from two independent cohorts. We established the associations of localized SYK with clinicopathologic variables and outcomes. The immunomodulatory role of SYK on tumor cells was assessed using in vitro cytokine stimulation, transcriptomic analysis and selective SYK blockade using a small molecule inhibitor. Functional responses were assessed using cocultures of tumor cells with peripheral blood lymphocytes. T cell responses in baseline and post-treatment biopsies from patients with BC treated with a SYK inhibitor in a phase I clinical trial were also studied. Elevated tumor cell or leukocyte SYK expression was associated with high CD4+ and CD8+ TILs and better outcome in both NSCLC and BC. Tumor cell SYK was associated with oncogenic driver mutations in EGFR or KRAS in lung adenocarcinomas and with triple negative phenotype in BC. In cultured tumor cells, SYK was upregulated by TNFα and required for the TNFα-induced proinflammatory responses and T cell activation. SYK blockade after nivolumab in a phase I clinical trial including three patients with advanced triple negative BC reduced TILs and T cell proliferation. Our work establishes the proinflammatory function of tumor cell SYK in lung and breast cancer. SYK signaling in cultured tumor cells is required for T cell activation and SYK blockade limits adaptive antitumor immune responses and tumor rejection in patients with cancer. Together, our results establish the immunomodulatory role of SYK expression in human solid tumors. This information could be used to develop novel biomarkers and/or therapeutic strategies.
Vitisin B inhibits influenza A virus replication by multi-targeting neuraminidase and virus-induced oxidative stress
Authors: Eun-Bin Kwon, Wei Li, Young Soo Kim, Buyun Kim, Hwan-Suck Chung, Younghoon Go, Hyun-Jeong Ko, Jae-Hyoung Song, Young Ho Kim, Chun Whan Choi, Jang-Gi Choi
Journal: Acta Pharmaceutica Sinica B (2022)

The development of drug-resistant influenza and new pathogenic virus strains underscores the need for antiviral therapeutics. Currently, neuraminidase (NA) inhibitors are commonly used antiviral drugs approved by the US Food and Drug Administration (FDA) for the prevention and treatment of influenza. Here, we show that vitisin B (VB) inhibits NA activity and suppresses H1N1 viral replication in MDCK and A549 cells. Reactive oxygen species (ROS), which frequently occur during viral infection, increase virus replication by activating the NF-κB signaling pathway, downmodulating glucose-6-phosphate dehydrogenase (G6PD) expression, and decreasing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response activity. VB decreased virus-induced ROS generation by increasing G6PD expression and Nrf2 activity, and inhibiting NF-κB translocation to the nucleus through IKK dephosphorylation. In addition, VB reduced body weight loss, increased survival, decreased viral replication and the inflammatory response in the lungs of influenza A virus (IAV)-infected mice. Taken together, our results indicate that VB is a promising therapeutic candidate against IAV infection, complements existing drug limitations targeting viral NA. It modulated the intracellular ROS by G6PD, Nrf2 antioxidant response pathway, and NF-κB signaling pathway. These results demonstrate the feasibility of a multi-targeting drug strategy, providing new approaches for drug discovery against IAV infection.
Mutation burden-orthogonal tumor genomic subtypes delineate responses to immune checkpoint therapy
Authors: Shiro Takamatsu, Junzo Hamanishi, J B Brown, Ken Yamaguchi, Koji Yamanoi, Kosuke Murakami, Osamu Gotoh, Seiichi Mori, Masaki Mandai, Noriomi Matsumura
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background In cancer therapy, higher-resolution tumor-agnostic biomarkers that predict response to immune checkpoint inhibitor (ICI) therapy are needed. Mutation signatures reflect underlying oncogenic processes that can affect tumor immunogenicity, and thus potentially delineate ICI treatment response among tumor types. Methods Based on mutational signature analysis, we developed a stratification for all solid tumors in The Cancer Genome Atlas (TCGA). Subsequently, we developed a new software (Genomic Subtyping and Predictive Response Analysis for Cancer Tumor ICi Efficacy, GS-PRACTICE) to classify new tumors submitted to whole-exome sequencing. Using existing data from 973 pan-cancer ICI-treated cases with outcomes, we evaluated the subtype-response predictive performance. Results Systematic analysis on TCGA samples identified eight tumor genomic subtypes, which were characterized by features represented by smoking exposure, ultraviolet light exposure, APOBEC enzyme activity, POLE mutation, mismatch repair deficiency, homologous recombination deficiency, genomic stability, and aging. The former five subtypes were presumed to form an immune-responsive group acting as candidates for ICI therapy because of their high expression of immune-related genes and enrichment in cancer types with FDA approval for ICI monotherapy. In the validation cohort, the samples assigned by GS-PRACTICE to the immune-reactive subtypes were significantly associated with ICI response independent of cancer type and TMB high or low status. Conclusions The new tumor subtyping method can serve as a tumor-agnostic biomarker for ICI response prediction and will improve decision making in cancer treatment.
Risk factors, mortality trends, and cardiovascular diseases in people with Type 1 diabetes and controls in Sweden: An observational cohort study
Authors: Sara Hallström, Magnus Olof Wijkman, Johnny Ludvigsson, Per Ekman, Marc Alan Pfeffer, Hans Wedel, Annika Rosengren, Marcus Lind
Journal: The Lancet Regional Health - Europe (2022)

Historically, the incidence of cardiovascular disease and mortality in persons with Type 1 diabetes (T1D) has been increased compared to the general population. Contemporary studies on time trends of mortality and cardiovascular disease are sparse.In this observational study, T1D persons were identified in the Swedish National Diabetes Registry (n=45,575) and compared with matched controls from the general population (n=220,141). Incidence rates from 2002 to 2019 were estimated with respect to mortality and cardiovascular disease in persons with T1D overall and when stratified for prevalent cardiovascular and renal disease relative to controls.Mean age in persons with T1D was 32.4 years and 44.9% (20,446/45,575) were women. Age- and sex- adjusted mortality rates declined over time in both groups but remained significantly higher in those with T1D compared to controls during 2017-2019, 7.62 (95% CI 7.16; 8·08) vs. 2.23 (95% CI 2.13; 2.33) deaths per 1,000 person years. Myocardial infarction, heart failure and stroke decreased over time in both groups, with persistent excess risks in the range of 3.4-5.0 times from 2017 to 2019 in those with T1D. T1D persons ≥45 years without previous renal or cardiovascular complications had standardized mortality rates similar or even lower than controls 5.55 (4.51; 6.60) vs.7.08 (6.75; 7.40) respectively in the last time period.Excess mortality persisted over time in persons with T1D, largely in patients with cardiorenal complications. Improved secondary prevention with a focus on individualized treatment is needed to close the gap in mortality for individuals with T1D.This study was financed by grants from the ALF-agreement, NovoNordisk Foundation and the Swedish Heart and Lung Foundation.
Corrections to “Quality of facility-based maternal and newborn care around the time of childbirth during the COVID-19 pandemic: Online survey investigating maternal perspectives in 12 countries of the WHO European Region”
Authors: Marzia Lazzerini, Benedetta Covi, Ilaria Mariani, Zalka Drglin, Maryse Arendt, Ingvild Hersoug Nedberg, Helen Elden, Raquel Costa, Daniela Drandić, Jelena Radetić, Marina Ruxandra Otelea, Céline Miani, Serena Brigidi, Virginie Rozée, Barbara Mihevc Ponikvar, Barbara Tasch, Sigrun Kongslien, Karolina Linden, Catarina Barata, Magdalena Kurbanović, Jovana Ružičić, Stephanie Batram-Zantvoort, Lara Martín Castañeda, Elise de La Rochebrochard, Anja Bohinec, Eline Skirnisdottir Vik, Mehreen Zaigham, Teresa Santos, Lisa Wandschneider, Ana Canales Viver, Amira Ćerimagić, Emma Sacks, Emanuelle Pessa Valente
Journal: The Lancet Regional Health - Europe (2022)

[This corrects the article DOI: 10.1016/j.lanepe.2021.100268.].
David John Williams
Authors: Lucy Andrews, Taj Hassan
Journal: BMJ (2022)

<h3>Objective:</h3> Our objective was to determine whether altered naive CD4 T-cell biology contributes to development of disease progression in secondary progressive multiple sclerosis (SPMS). <h3>Methods:</h3> We compared the naive CD4 T-cell gene expression profiles of 19 patients with SPMS and 14 healthy controls (HCs) using a whole-genome microarray approach. We analyzed surface protein expression of critical genes by flow cytometry after T-cell receptor (TCR) stimulation of naive CD4 T cells isolated from HCs and patients with SPMS. <h3>Results:</h3> Hierarchical clustering segregated patients with SPMS into 2 subgroups: SP-1, which had a short duration of relapsing-remitting multiple sclerosis (MS), and SP-2, which had a long duration of relapsing-remitting MS. SP-1 patients upregulated numerous immune genes, including genes within TCR and toll-like receptor (TLR) signaling pathways. SP-2 patients showed immune gene downregulation in comparison with HCs. We identified an SP-1–specific transcriptional signature of 3 genes (<i>TLR4</i>, <i>TLR2</i>, and chemokine receptor 1), and these genes had higher surface protein expression in SP-1 than in SP-2. After TCR stimulation for 48 hours, only SP-1 showed a progressive linear increase in TLR2 and TLR4 protein expression. <h3>Conclusions:</h3> Differences in naive CD4 T-cell biology, notably of TCR and TLR signaling pathways, identified patients with MS with more rapid conversion to secondary progression, a critical determinant of long-term disability in MS.
Building a home ventilation programme: population, equipment, delivery and cost
Authors: Michel Toussaint, Peter J Wijkstra, Doug McKim, Joshua Benditt, Joao Carlos Winck, Jacek Nasiłowski, Jean-Christian Borel
Journal: Thorax (2022)

Home mechanical ventilation (HMV) improves quality of life and survival in patients with neuromuscular disorders (NMD). Developing countries may benefit from published evidence regarding the prevalence, cost of equipment, technical issues and organisation of HMV in NMD, facilitating the development of local turn-key HMV programmes. Unfortunately, such evidence is scattered in the existing literature. We searched Medline for publications in English and French from 2005 to 2020. This narrative review analyses 24 international programmes of HMV. The estimated prevalence (min–max) of HMV is ±7.3/100 000 population (1.2–47), all disorders combined. The prevalence of HMV is associated with the gross domestic product per capita in these 24 countries. The prevalence of NMD is about 30/100 000 population, of which ±10% would use HMV. Nocturnal (8/24 hour), discontinuous (8–16/24 hours) and continuous (&gt;16/24 hours) ventilation is likely to concern about 60%, 20% and 20% of NMD patients using HMV. A minimal budget of about 168€/patient/year (504€/100 000 population), including the cost of equipment solely, should address the cost of HMV equipment in low-income countries. When services and maintenance are included, the budget can drastically increase up to between 3232 and 5760€/patient/year. Emerging programmes of HMV in developing countries reveal the positive impact of international cooperation. Today, at least 12 new middle, and low-income countries are developing HMV programmes. This review with updated data on prevalence, technical issues, cost of equipment and services for HMV should trigger objective dialogues between the stakeholders (patient associations, healthcare professionals and politicians); potentially leading to the production of workable strategies for the development of HMV in patients with NMD living in developing countries.
Intravenous iron therapy improves the hypercapnic ventilatory response and sleep disordered breathing in chronic heart failure
Authors: Sergio Caravita, Andrea Faini, Carlo Vignati, Sara Pelucchi, Elisabetta Salvioni, Gaia Cattadori, Claudia Baratto, Camilla Torlasco, Mauro Contini, Alessandra Villani, Gabriella Malfatto, Elisa Perger, Carolina Lombardi, Alberto Piperno, Piergiuseppe Agostoni, Gianfranco Parati
Journal: European Journal of Heart Failure (2022)

Intravenous iron therapy can improve symptoms in patients with heart failure, anaemia and iron deficiency. The mechanisms underlying such an improvement might involve chemoreflex sensing and nocturnal breathing patterns.Patients with heart failure, reduced left ventricular ejection fraction, anaemia (haemoglobin <13 g/dl in men; <12 g/dl in women) and iron deficiency (ferritin <100 or 100-299 μg/L with transferrin saturation <20%) were 2:1 randomized to patient-tailored intravenous ferric carboxymaltose dose or placebo. Chemoreflex sensitivity cardiorespiratory sleep study, symptom assessment and cardiopulmonary exercise test were performed before and 2 weeks after the last treatment dose. Fifty-eight patients (38 active arm/20 placebo arm) completed the study. Intravenous iron was associated with less severe symptoms, higher haemoglobin (12.5 ± 1.4 vs. 11.7 ± 1.0 mg/dl, p < 0.05) and improved haematinic parameters. Ferric carboxymaltose improved the central hypercapnic ventilatory response (-25.8%, p < 0.05 vs. placebo), without changes in peripheral chemosensitivity. In particular, the central hypercapnic ventilatory responses passed from 4.6 ± 6.5 to 2.9 ± 2.9 L/min/mmHg after ferric carboxymaltose and from 4.4 ± 4.6 to 4.6 ± 3.9 L/min/mmHg after placebo (ptreatment*condition = 0.046). In patients presenting with sleep-related breathing disorder, apnoea-hypopnoea index was reduced with active treatment as compared to placebo (12 ± 11 vs. 19 ± 13 events/h, p < 0.05). After ferric carboxymaltose, but not after placebo, both peak oxygen uptake (VO2 ) increased (Δ1.1 ± 2.0 ml/kg/min, p < 0.05) and VO2 /workload slope was steeper (Δ0.67 ± 1.7 L/min/W, p < 0.01).Intravenous ferric carboxymaltose improves the hypercapnic ventilatory response and sleep-related breathing disorders in patients with heart failure, anaemia and iron deficiency. These newly described findings, along with improved oxygen delivery to exercising muscles, likely contribute to the favourable effects of ferric carboxymaltose in anaemic patients with heart failure.